Economic evaluation. Elucigene and LIPOchip for the diagnosis of familial hypercholesterolemia.
Eric Sijbrands Erasmus University Medical Center Rotterdam Mortality from familial...
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Transcript of Eric Sijbrands Erasmus University Medical Center Rotterdam Mortality from familial...
Eric SijbrandsEric Sijbrands
Erasmus University Erasmus University Medical CenterMedical CenterRotterdamRotterdam
Mortality from familial Mortality from familial hypercholesterolemia (FH)hypercholesterolemia (FH)
Eric SijbrandsEric Sijbrands
Eric Sijbrands is consultant in internal medicine and head of the lipid clinic of the Erasmus University Medical Center Rotterdam. After he obtained his qualification as medical doctor in 1990, he was given the opportunity to receive his training in internal medicine and to work in scientific research at the Universities of Leiden and Amsterdam. He made a Ph.D. thesis on gene-gene and gene-environment interaction in patients with genetic hyperlipidemia. His present research is focussed on genetic epidemiology of cardiovascular disease (hyperlipidemia, diabetes mellitus, and pharmacogenetics of hypertension).
resumeresume
Learning objectivesLearning objectives
selection on outcome standardization burden of monogenetic disorder genetic heterogeneity gene-environment interaction
Performance objectivesPerformance objectives
understand the clinical consequences of monogenetic disorders
FH - characteristicsFH - characteristics
autosomal dominantautosomal dominant heterozygosity 1:500heterozygosity 1:500 mutations in the LDL receptor mutations in the LDL receptor
gene on chromosome 19gene on chromosome 19 total cholesterol > 8 mmol/Ltotal cholesterol > 8 mmol/L tendon xanthomastendon xanthomas
introductionintroduction
FH - what is already knownFH - what is already known
cardiovascular diseasecardiovascular diseaseat young ageat young age
excess mortalityexcess mortality
population data are lackingpopulation data are lacking
introductionintroduction
Burden of untreated FHBurden of untreated FHintroductionintroduction
analyses of mortality in:
a large pedigree‘free from selection on CVD’
113 small pedigreesreferred to a lipid clinic
Monogenetic disorderMonogenetic disorder
cause disease death
introductionintroduction
Monogenetic disorderMonogenetic disorderintroductionintroduction
additional factors
cause disease death
Natural historyNatural historyintroductionintroduction
Large pedigree: FH-V408MLarge pedigree: FH-V408M
Sijbrands EJG, et al. BMJ 2001;322:1019-23.
introductionintroduction
StandardizationStandardization
SMR = observed / expected deaths
strata per genderstrata per age categorystrata per calendar period
introductionintroduction
SMRSMR
V408M death p.y. SMR (95%CI)
50% 70 6950 1.32 (1.03-1.67) 100% 30 3186 1.59 (1.07-2.26)
large pedigreelarge pedigree
SMRSMRlarge pedigreelarge pedigree
Calendar period
1840 1870 1900 1930 1960 1990
SM
R
0.5
1.0
2.0
3.0
MalesFemales
Kaplan-MeierKaplan-Meierlarge pedigreelarge pedigree
Conclusion 1Conclusion 1
gene-environment
interaction
large pedigreelarge pedigree
113 small pedigrees113 small pedigrees
number
cardiologist 39GP 51insurance 4other 19
total 113
outpatient lipid clinicoutpatient lipid clinic
Sijbrands EJG, et al. Atherosclerosis 1998;136:247-54.
characteristic n=113
male / female 55/58age 48 (20 to 69)xanthomas 66cholesterol 11.04 mmol/L
113 FH patients113 FH patientsoutpatient lipid clinicoutpatient lipid clinic
SMRSMR
age deaths p.y. SMR (95%CI) 1- 19 6 11091 0.45 (0.17-0.98)20- 39 12 10796 1.01 (0.52-1.76)40- 54 43 6317 1.88 (1.36-2.53)55- 69 69 2973 1.76 (1.36-2.22)70- 79 38 688 1.22 (0.87-1.68)80-103 22 184 0.96 (0.60-1.46)
1-103 190 32048 1.34 (1.16-1.55)
outpatient lipid clinicoutpatient lipid clinic
SMRSMR
Age (years)
30 50 70 90
SM
R
0.5
1.0
2.0
3.0
MalesFemales
outpatient lipid clinicoutpatient lipid clinic
Other risk factorsOther risk factors
premature CVD SMR 95% CI
– (51 families) 1.10 0.86-1.34
+ (62 families) 1.62 1.32-1.93
RR+ versus – 1.46 1.09-1.94
outpatient lipid clinicoutpatient lipid clinic
Type of LDLR mutationType of LDLR mutation
characteristic mRNA + mRNA - p(n=24) (n=14)
male, % 58 43 0.4age 50 47 0.4BMI 25.1 25.1 1.0xanthomas, % 42 93 0.001LDL-C 8.86 10.21 0.04HDL-C 1.20 1.04 0.05
outpatient lipid clinicoutpatient lipid clinic
Type of LDLR mutationType of LDLR mutationoutpatient lipid clinicoutpatient lipid clinic
Conclusion 2Conclusion 2
other risk factors for CVD
type of mutation is not relevant
outpatient lipid clinicoutpatient lipid clinic
FH - what these studies addFH - what these studies add
many untreated patients (40%) reach a normal life span
burden of FH depends on time variation in mortality suggests an
interaction between genetic and environmental CVD risk factors
Future ...Future ...
individual risk–molecular diagnosis–additional genes–environmental factors
exact indication for
tailored intervention